Although it is known that calcitonin (CT) is a pharmacological inhibitor of bone resorption and calcitonin gene-related product (CGRP) is a potent vasodilator and neuropeptide, the physiologic role for these related peptides remains unproved. The CALC I and CALC II genes encode for CGRP. Transcription of CALC I results in an mRNA coding for both CT and CGRP-I. CALC II produces only CGRP (CGRP-II). The two CGRP peptides are highly homologous with unique, at times overlapping, tissue distributions. To dissect the contributions of these closely related hormones to normal mammalian development and physiology, animal models containing null mutations at each locus will be generated. To accomplish this, each gene will be selectively eliminated using the technique of targeted gene disruption in pluripotent mouse embryonic stem (ES) cells.